1 Risk of Drug-Induced Long QT Syndrome Associated with the Use

medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review. Veronique Michaud,1,2 BPharm, PhD, Chief Operating Officer, [email protected] Pamela Dow,1 MS, Clinical Research Manager, [email protected] Sweilem B. Al Rihani,1 PharmD, PhD, Clinical Research Scientist, [email protected] Malavika Deodhar,1BPharm, PhD, Clinical Research Scientist, [email protected] Meghan Arwood,1 PharmD, Clinical Research Scientist, [email protected] Brian Cicali,3 MSc, PhD Student, Pharmaceutics, [email protected] Jacques Turgeon,1,2 BPharm, PhD, Chief Scientific Officer, [email protected] 1. Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, Florida, 32827, USA 2. Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, H3C 3J7, Canada 3. College of Pharmacy, Lake Nona Campus, University of Florida, Orlando, Florida, 32827, USA

Abstract Background: The World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored. Methods: A thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current

(IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds. Results: Estimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug- induced LQTS for the 6 repurposed drugs and the 23 torsadogenic compounds. Conclusion: The risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systemic review

Veronique Michaud, Pamela Dow, Sweilem B Al Rihani, Malavika Deodhar, Meghan Arwood, Brian Cicali, and Jacques Turgeon.

Veronique Michaud, BPharm, PhD (0000-0002-0504-5502) Chief Operating Officer, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected], Pamela Dow, MS, Clinical Research Manager, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected], Sweilem B. Al Rihani, PharmD, PhD, Clinical Research Scientist, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected], Malavika Deodhar, BPharm, PhD, Clinical Research Scientist, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected], Meghan Arwood, PharmD, Clinical Research Scientist, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected], Brian Cicali, MSc, PhD Student, University of Florida Center for Pharmacometrics and Systems Pharmacology, 6550 Sanger Road, Orlando, FL 32827, [email protected], Jacques Turgeon, BPharm, PhD (0000-0002-7978-9280), Chief Scientific Officer, Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA, [email protected] Correspondence to: Jacques Turgeon, B.Pharm., Ph.D. (0000-0002-7978-9280) Chief Scientific Officer, Tabula Rasa HealthCare, 13485 Veteran’s Way, Suite 410, Orlando, Florida, 32827, USA

Acknowledgements: The authors want to thank Dana Filippoli and Dr. Calvin H. Knowlton for review and insightful comments on the content of the paper. The authors also recognize the contribution of Ernesto Lucio, Gerald Condon, Ravil Bikmetov, PhD, and Matt K Smith, PhD.

Disclosure Statement: Jacques Turgeon, Veronique Michaud, Pamela Dow, Sweilem Al Rihani, Malavika Deodhar, and Meghan Arwood are employees of Tabula Rasa HealthCare. Brian Cicali is a former employee of Tabula Rasa HealthCare and is currently an independent contractor. Jacques Turgeon and Veronique Michaud are faculty at the Université de Montréal.

2 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

ABSTRACT

Background: The World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored. Methods: A thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current

(IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds. Results: Estimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug- induced LQTS for the six repurposed drugs and the 23 torsadogenic compounds. Conclusion: The risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

3 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

INTRODUCTION

Repurposing of Drugs for COVID-19 Over the last two decades, the world has experienced a number of pandemics, including SARS-CoV-1 (Severe Acute Respiratory Syndrome – Coronavirus), Swine Flu, MERS-CoV (Middle East Respiratory Syndrome - Coronavirus), and now, SARS-CoV-2. Unique to these pandemics is that each is believed to have originated in animals and spread to humans, and each resulted in respiratory infection.1-4 First reported in February 2003, SARS-CoV-1 originated in Asia and spread to more than twelve countries on four continents in three months, infecting 8,422 people and killing 916 (10.8%).2 MERS-CoV was retrospectively determined to have originated in Jordan in April 2012. At the end of November 2019, MERS-CoV had been diagnosed in 2,494 people, of whom approximately 35% have died.3, 5 The World Health Organization (WHO) first declared SARS-CoV-2 infection (COVID-19) a pandemic on March 11, 2020.6 Originating in Wuhan, China in 2019, WHO was first notified about this viral respiratory illness on December 31, 2019. As of April 21, 2020, there are 2,501,156 confirmed cases worldwide, with 171,810 confirmed deaths (6.87%), in 185 countries.7 As the virus continues to spread, there is an urgent need to develop and find an effective treatment. There are currently no vaccines or proven therapeutic agents to treat COVID-19. So, whether existing approved drugs could be repurposed and used for the treatment of novel COVID-19 disease is being explored. As of April 21, 2020, there are 725 clinical trials registered for COVID-19, many assessing drugs to be repurposed for use against COVID-19: among those, chloroquine, hydroxychloroquine, lopinavir/ritonavir and remdesivir.8 There have been a few promising preliminary in vitro results using some repurposed drugs in the therapeutic management of COVID-19, selected based upon their mechanism of action. Yet, the risk of doing so in COVID-19 cases has not been quantified.9 Whether or not a drug is used appropriately and safely, the administration of repurposed drugs may lead to serious, even fatal, consequences. A systematic approach should be used to assess risk benefit boundaries with the proposed repurposed drugs. The uncertainty about the clinical benefit should be balanced with risk of toxicity to justify the use of unproven indications. Furthermore, safety profiles of repurposed drugs might be different if they have never been used or tested in such different populations of patients. This is especially true if they have a complex drug regimen with polypharmacy and are treated with other narrow therapeutic index drugs. The American College of Cardiology (ACC) has recently issued a warning regarding the use of some of these drugs without evidence of whether their benefits outweigh their risks.10 Drugs like hydroxychloroquine and chloroquine prolong the QT interval, and may cause ventricular arrythmia and

4 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

sudden cardiac arrest. Our team is currently conducting a risk assessment study using simulations in specific populations of patients in whom these repurposed drugs could most likely be associated with unbalanced risk of cardiac toxicity (NCT04339634, Simulation of Risk of Adverse Drug Events Associated with the Initiation of Drugs Repurposed for the Treatment of COVID-19 in Frail Elderly Adults with Polypharmacy).11 This review will look at drugs proposed as potential COVID-19 therapies, assessing their risk of causing QT prolongation and their proarrhythmic properties that lead to a characteristic polymorphic ventricular tachycardia described as torsade de pointes (TdP).12 QT and Drug-induced Long QT Syndrome (LQTS) The QT interval of the cardiac electrocardiogram is the time period needed for depolarization and repolarization of ventricular myocytes. Human cardiac ventricular myocytes are mainly repolarized by the activity of outward K+ currents, and QT prolongation is mainly caused by delayed repolarization. One

+ of the major currents is the delayed rectifier K current IK, which consists of a rapidly (IKr) and a slowly

13 (IKs) activating component. The human ether-a-go-go-related gene (hERG; KCNH2) encodes the α- + 14, 15 subunit of the voltage gated K channels underlying the native current IKr. Inhibition of the hERG

proteins (IKr current) can lead to a prolongation of the action potential duration and consequently of the QT interval; when repolarization is prolonged to an extreme, early afterdepolarizations may be

16 generated which may lead to TdP. The slow component of IK, IKs, is encoded by Kv7.1 (KCNQ1) and could be the target of some diuretics such as indapamide or triamterene, or anesthetics such as

17-19 20 propofol. Excessive block of IKs and/or combined block of IKr and IKs could also lead to TdP. LQTS is a medical condition resulting from polymorphic ventricular tachyarrhythmia which can lead to sudden cardiac arrest under certain circumstances. Congenital LQTS is the inherited form caused by genetic mutations in several genes, the most important ones being KCNQ1, KNCH2 and SCN5A (the

21-26 sodium current INa). Acquired LQTS is by far the most prevalent form of LQTS; the incidence rate of drug-induced LQTS is estimated at 0.8 to 1.2 per million person-per year.27, 28 The vast majority of acquired LQTS results from specific medications and/or electrolyte abnormalities.29 Drug-induced LQTS

is predominantly associated with serious blocking of hERG channels and the subsequent decrease in IKr current. There is a wide range of pharmacological agents in different therapeutic classes known to block

30 IKr and induce QT prolongation, including type III antiarrhythmics and various drugs prescribed for non- cardiovascular indications such as antibiotics (e.g. clarithromycin), antidepressants (e.g. tricyclics, selective serotonin reuptake inhibitors), antipsychotics (e.g. haloperidol, pimozide), antiemetics (e.g. ondansetron) and antimalarial drugs (e.g. chloroquine, hydroxychloroquine).29

5 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

The relationship between the potency of a compound to block IKr and the likelihood to prolong QT and

to induce TdP is unclear. In addition, no clear structure activity relationships related to a risk of IKr

inhibition has been elucidated. However, it is generally accepted to consider a high potency (low IC50-

value) for IKr inhibition as a risk factor for fatal arrhythmias related to QT interval prolongation. This is

especially true if the free therapeutic plasma concentration of a drug is near or even below the IC50- 31 value for IKr inhibition. To compare the proarrhythmic potential of drugs, it is reasonable to calculate various cardiac safety indices.32, 33

The purpose of this article is to assess the proarrhythmic potential with regard to IKr inhibition of proposed repurposed drugs for COVID-19. Various risk assessments for drug-induced LQTS will be presented and compared as a predictive estimator for unbalanced risk benefit associated with repurposed drugs for COVID-19.

METHODS

STEP 1: A literature search was conducted using the National Library of Medicine (https://pubmed.ncbi.nlm.nih.gov/). A primary search used the key words “drug-induced QT prolongation index”. From this search, 38 publications were retrieved and considered for analysis. Six different indices were repeatedly referenced, including methodology and data on large numbers of drugs or elements to consider while evaluating the risk of drug-induced Long QT Syndrome. The retained indices are discussed in the Results and Discussion section. We also included for comparison our Long QT-JT index (Patent #PCT/US2017/033539, United States of America, 2017). STEP 2: A search was performed using pubmed.gov with the following keywords (number of publications retrieved and analyzed are included in parentheses): “azithromycin and QT” (80), “azithromycin and torsade” (35), “azithromycin and arrhythmia” (97), “chloroquine and QT” (50), “chloroquine and torsade” (17), “chloroquine and arrhythmia” (178), “favipiravir and QT” (2), “favipiravir and torsade” (0), “favipiravir and arrhythmia” (1), “hydroxychloroquine and QT” (16), “hydroxychloroquine and torsade” (3), “hydroxychloroquine and arrhythmia” (58), “lopinavir/ritonavir and QT” (8), “lopinavir/ritonavir and torsade” (7), “lopinavir/ritonavir and arrhythmia” (19), “remdesivir and QT” (0), “remdesivir and torsade” (0), and “remdesivir and arrhythmia” (0). STEP 3: A similar search was conducted by combining the key words “QT”, “torsade”, and “arrhythmia” with 19 “Known Risk”, 3 “Possible Risk” and 1 “Conditional Risk” torsadogenic drugs as reported by CredibleMeds® (https://www.crediblemeds.org/). These drugs were: “astemizole, chlorpromazine,

6 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

cilostazol, cisapride, clarithromycin, clozapine, dasatinib, domperidone, donepezil, droperidol, escitalopram, halofantrine, haloperidol, lapatinib, methadone, ondansetron, pentamidine, pimozide, propofol, risperidone, terfenadine, thioridazine, and vandetanib”.

STEP 4: Pharmacological information [IC50 for hERG (IKr) block, IC50 for Nav1.5 (INa) block, IC50 for Cav1.2

(ICa-L) block, IC50 for IKs block, Cmax, maximum daily dose, plasma protein binding, inhibition of hERG

trafficking, cardiac action potential duration (at 90% repolarization; APD90)] and clinical information (QT prolongation, torsade de pointe), retrieved from STEPs 2 and 3 were used to compute relevant QT indices retained from our analysis in STEP 1 for 6 COVID-19 repurposed drugs and 23 known torsadogenic drugs. STEP 5: Codes to performed a query to the US Food and Drug Administration Adverse Event Reporting System (FAERS) were written for each of the 6 COVID-19 repurposed drugs and 23 known torsadogenic drugs searching for adverse events reported for these drugs and a combination of specific search terms: “Electrocardiogram QT prolonged, Long QT Syndrome, Long QT Syndrome congenital, Torsade de pointes, Ventricular tachycardia, Cardiac arrest, Cardiac death, Cardiac fibrillation, Cardio-respiratory arrest, Electrocardiogram repolarization abnormality, Electrocardiogram U wave inversion, Electrocardiogram U wave present, Electrocardiogram U-wave abnormality, Loss of consciousness, Multiple organ dysfunction syndrome, Sudden cardiac death, Sudden death, Syncope, Ventricular arrhythmia, Ventricular fibrillation, Ventricular flutter, Ventricular tachyarrhythmia, Ventricular tachycardia, Cardiac arrest and Cardio-respiratory arrest”.

RESULTS AND DISCUSSION

Assessing risk of drug-induced LQTS. Several approaches have been proposed to assess risk of drug-induced LQTS. Among the most important were the S7B and E14 International Conference on Harmonisation Guidances for non-clinical and clinical evaluation of new non-antiarrhythmic human pharmaceuticals.34, 35 After the introduction of these guidelines in 2005, no drugs were removed from the market due to TdP risk. However, concerns were raised that the optimal fail-fast fail-safe paradigm in recent drug development programs led to unnecessary removal of promising therapeutic molecules.36 There were also concerns regarding the financial burden associated with these types of studies; therefore, alternative approaches were evaluated.37

7 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

In 2003, Redfern et al. published an exhaustive review on a broad range of drugs looking at hERG (IKr) 38 activity, cardiac action potential duration (at 90% repolarization; APD90), and QT prolongation in dogs. They compared these properties against QT prolonging effects of drugs and reports of TdP in humans. The investigators considered the free plasma concentrations attained during clinical use and classified drugs into five categories.36 Category 1 includes repolarization-prolonging antiarrhythmics; Category 2 includes drugs that have been withdrawn or suspended from the market in at least one major regulatory territory due to an unacceptable risk of TdP for the condition being treated; Category 3 includes drugs that have a measurable incidence of TdP in humans, and those for which numerous case reports exist in the published literature; Category 4 includes drugs for which there have been isolated reports of TdP in humans; and Category 5 includes drugs for which there have been no published reports of TdP in humans. In 2013, Kramer et al. assessed concomitant block of multiple ion channels (Multiple Ion Channel Effects,

MICE) by measuring the concentration-responses of hERG (IKr), Nav1.5 (INa) and Cav1.2 (ICa-L) currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple pharmacological classes.39 The best logistic regression models using the MICE assay only required a comparison of the blocking potencies between hERG and Cav1.2. Unfortunately, drug-specific indices or values associated with their drug

comparison model were not provided. Other much simpler indices such as K/Cmax, i.e., IC50, for block of

IKr/peak plasma concentration (Cmax at maximum dose) or K/ Cmax free, i.e. IC50 for block of IKr/ Cmax unbound concentration (considering plasma protein binding) have also been proposed.38 Values ≤3 and ≤30 for these respective factors are generally considered indicative of high risk of drug-induced LQTS. More recently, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was established by a partnership of the United States Food and Drug Administration (FDA), Health and Environmental Sciences Institute (HESI), Cardiac Safety Research Consortium (CSRC), Safety Pharmacology Society (SPS), European Medicine Agency (EMA), Health Canada and Japan National Institute of Health Sciences (NIHS). Their main objective was to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms

40 beyond IKr block. Their strategy involves three pillars to evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). In their most recent publication, they reported on a list of 28 drugs under three risk categories.41 Their High TdP Risk category includes mostly Class III or Class 1A antiarrhythmics; their Intermediate Risk category groups drugs that are generally

8 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

accepted to be torsadogenic; and the Low Risk category included drugs known not to be associated with TdP. Other groups have concentrated their efforts on creating in silico tools for the early detection of drug- induced proarrhythmic risks.42, 43 For instance, Romero et al. looked at the effects of drugs on action potential duration of isolated endocardial, myocardial, and epicardial cells as well as the QT prolongation in virtual tissues using multiple channel-drug interactions and state-of-the-art human ventricular action potential models.44 Based on 206,766 cellular and 7,072 tissue simulations assessing

block of IKr, IKs and ICa-L, they studied 84 compounds and classified 40 of them as torsadogenic. They proposed the use of a new index, Tx, for differentiating torsadogenic compounds. Tx was defined as the

ratio of the drug concentrations producing 10% prolongation (similar to an IC10 rather than IC50) of the cellular endocardial, midmyocardial, and epicardial APDs, and the QT interval, over the maximum effective free therapeutic plasma concentration. For many years, a group led by Dr. Raymond Woosley has accumulated information on drugs associated with LQTS.45 CredibleMeds® reviews available evidence for these drugs and places them into one of three designated categories: Known Risk of TdP, Possible Risk of TdP, and Conditional Risk of TdP. They have also created a list of drugs to avoid in patients with genetically inherited LQTS. The merit of CredibleMeds® is the classification of drugs based on clinically observed and documented cases of TdP of QT prolongation. Another approach to assess risk of drug-induced LQTS is using the FDA Adverse Event Reporting System (FAERS), a database developed to support the FDA’s post-marketing safety surveillance program that monitors occurrence of 104 classified side-effects for drugs and therapeutic biologic products. This database contains information on adverse drug events and medication error reports submitted to the FDA. Although it presents some limitations, the appropriate adjustment of this data allows the capture of signals suggesting adverse drug events associated with a particular drug. On an individual and/or population basis, FAERS data can be used to identify patients who are at highest risk of adverse drug events. Therefore, our team is currently using such information to feed algorithms calculating the relative odd ratios to enable the computation of a medication risk score (MedWise Risk ScoreTM), as part of our proprietary risk stratification strategy.46 All of the sus-mentioned approaches are complementary while each having their own weaknesses and strengths. Recognizing the complexity of determining the risk of drug-induced LQTS noted by others47,

our team has developed the Long QT-JT index, which uses algorithms that consider IC50 for block of

relevant ion channels (IKr, IKs, INa, ICa-L), inhibition of hERG trafficking, unbound Cmax at maximum dose,

9 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

and most importantly the inhibition of the major metabolic pathway involved in the disposition or torsadogenic drugs.48-50 This last factor is considered to be a major determinant of risk associated with drug-induced LQTS when torsadogenic drugs are co-administered with other drugs in patients with

polypharmacy. On one hand, it is often stated that combined administration of IKr blocking drugs (expected synergistic pharmacodynamic effects) could lead to increased QT prolongation. Although this

appears to be the case, our studies have demonstrated that concomitant block of IKr was not necessarily associated with synergistic or potentiation of drug effects.51 However, our team has shown that a

20 combined block of IKr and IKs was associated with potentiation of drug effects on cardiac repolarization. On the other hand, the role of competitive inhibition (pharmacokinetic interactions) due to inhibition of the metabolism of the torsadogenic drug, leading to its increased systemic exposure, is recognized but often overlooked.52-54 For the Long QT-JT index, a value ≤15 is associated with an increased risk of QT prolongation and induction of TdP by the drug, while a value >15 and ≤100 is associated with an increased risk of QT prolongation. Arrhythmogenic effects of COVID-19 drugs should be expected, potentially contributing to disease outcome.55 This may be of importance for patients with an increased risk for cardiac arrhythmias, either secondary to acquired conditions or co-morbidities or consequent to inherited syndromes.56 Various algorithms have been reported to identify patients that are more susceptible to experiencing drug

induced QT prolongation.57-59 Risk of drug-induced LQTS for repurposed off-label COVID-19 drugs This section describes the most significant pharmacological properties of selected proposed repurposed

drugs to be used off-label for the treatment of COVID-19; the effects of each of these drugs on IKr block is highlighted. Using the various approaches described above, the risk of COVID-19 repurposed drugs to induce LQTS (Table 1) is compared to the risk measures of 23 well-established, torsadogenic drugs (Table 2). Our team also presents the number of arrhythmogenic adverse drug events reported by the FAERS database for all drugs listed in Table 1 and 2 (Table 3). It is recognized that some bias certainly exists in the number of events reported by FAERS, as these events are not normalized for number of observed reports or prescriptions. Azithromycin. Azithromycin is indicated for the treatment of patients with mild to moderate infections such as acute bacterial exacerbations of chronic obstructive pulmonary disease, acute bacterial sinusitis, community-acquired pneumonia, pharyngitis/tonsillitis, uncomplicated skin and skin structure infections, urethritis and cervicitis, and genital ulcer disease in men.60 Its use has been proposed in conjunction with chloroquine or hydroxychloroquine to prevent or treat concomitant bacterial

10 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

infections in patients with COVID-19.61 Azithromycin is primarily excreted unmetabolized in the bile and less than six percent of the administered dose is found as unchanged drug in urine (over a one-week period).62 Peak plasma concentrations in the range of 400 ng/mL (550 nM) are observed following a single 500 mg oral dose.62-64 Rare cases of serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported in patients on azithromycin therapy.65 Other major side-effects include hepatotoxicity and Clostridium difficile-associated diarrhea.60 QT prolongation and TdP. Prolongation of cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and TdP, has been reported in patients treated with macrolides.66 All estimators of azithromycin-related risk of drug-induced TdP (Table 1) suggest a weak proarrhythmic

effect of the drug (IC50 for block of hERG between 0.856 mM and 1.091 mM), although cases of TdP have been described.67, 68 Furthermore, cases of TdP have been spontaneously reported during post- marketing surveillance (FAERS) in patients receiving azithromycin (Table 3). This explains why CredibleMeds® lists azithromycin as a “Known Risk” drug. Chloroquine. Chloroquine, approved by the FDA in 1949, was the drug of choice to treat malaria until the commercialization of newer antimalarials such as artemisinin (ATC combinations), mefloquine, or atovaquone/proguanil.69 The drug is also indicated for the treatment of extraintestinal amebiasis.70 Chloroquine is metabolized by CYP2C8 and CYP3A4 through dealkylation to monedethylchloroquine and

71, 72 bisdesethylchloroquine. Peak plasma concentrations (Cmax) of chloroquine in the range of 1.0-3.0 μM have been measured following the oral administration of a 600 mg oral dose to healthy subjects or patients.73-79 Severe and most common side-effects include retinopathy/maculopathy, macular degeneration, reduced hearing in patients with preexisting auditory damages, skeletal muscle myopathy or neuromyopathy (leading to progressive weakness and atrophy of proximal muscle groups), increased liver enzymes, anorexia, nausea and vomiting, pleomorphic skin eruptions, convulsive seizures, extrapyramidal disorders, and neuropsychiatric changes.70

30 QT prolongation and TdP. Chloroquine has been shown to block hERG channels with an IC50 of 2.5 μM. Redfern et al. described chloroquine as a Category 4 drug, i.e., drugs for which there have been isolated reports of TdP in humans.38 Indeed, case reports of chloroquine-induced QT prolongation, cardiac electrophysiology disturbance and TdP have been reported.53, 80, 81 Based on CredibleMeds® classification, chloroquine is a drug of “Known Risk” for TdP.45 The Long QT-JT index calculated for chloroquine under conditions of CYP2C8 inhibition is 3.56 (Table 1), a risk-estimate value similar to that calculated for drugs such as astemizole, haloperidol, pimozide and terfenadine (Table 2).48-50

11 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Favipivarir. Favipiravir is a new antiviral drug with a broad activity toward RNA viruses, such as the influenza virus, including the avian influenza (H5N1), rhinovirus and respiratory syncytial virus.82-84 It is currently considered as a potential treatment for COVID-19.85 Favipiravir is a prodrug that is ribosylated and phosphorylated intracellularly to form the active metabolite favipiravir ibofuranosyl-5- triphosphate (T-705RTP). T-705 undergoes conversion into a nucleotide analogue, with monophosphate (T-705 RMP occurs in one step via hypoxanthine-guanine phosphoribosyltransferase) and triphosphate (T-705 RTP enzymes responsible for the conversion from RMP to RDP not identified) derivatives. It is believed that T-705 potency is mediated by its ribofuranosyl triphosphate (T-705 RTP) metabolite that could be mutagenic.86 The usual adult dosage is 1,600 mg of favipiravir administered orally twice daily on day one, followed by 600 mg orally twice daily from day two through day five. Favipiravir has an excellent bioavailability (98%) and is not metabolized by the CYP450 system (it is mainly metabolized by aldehyde oxidase and partially by xanthine oxidase).87 In vitro studies indicated that the drug is a mechanism-based inhibitor of aldehyde oxidase which is known to contribute, to some extent, to the metabolism of citalopram, zaleplon, famciclovir and sulindac.88 However, it can inhibit sulfate

transferase with an IC50 value of (24 μg/mL) as Cmax in plasma is about 500 μM (78.9 μg/mL; 1,600 mg). It

88 could also inhibit CYP2C8 with an IC50 of 477 μM (74.9 μg/ml)). QT prolongation and TdP. Studies looking at the effects of favipiravir on hERG block have shown that a mild suppression of the hERG current was observed at the concentration of 1 mM (157 µg/mL, 2.0 times

the observed human Cmax at a dose of 1,600 mg). In a telemetry study conducted in dogs, no effects on blood pressure (systolic, diastolic, mean), heart rate, or ECG parameters (PR interval, QRS, QT and QTc)

were observed even at the oral dose of 150 mg/kg [Cmax (mean), 268 µg/mL; 3.4 times the human Cmax)] 88 until 20 hours have passed after the treatment. Calculation of K/ Cmax, K/ Cmax free and Long QT-JT Index

using an estimated IC50 of 5 mM (5-times the concentration associated with 8.1% block of IKr) yielded parameters in the high to very high-risk categories for drug-induced LQTS. As no reports of LQTS have

been published yet, close monitoring of QTc remains advisable. Hydroxychloroquine. Hydroxychloroquine is indicated for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, and P. vivax.89 It is also indicated for the treatment of rheumatoid arthritis and lupus erythematosus.89 Major metabolic pathway is through N-dealkylation leading to the formation of desethylhydroxychloroquine; desethylchloroquine and bisdesethylchloroquine are minor metabolites. The N-desalkylation pathway seems to be mediated by CYP2C8, CYP3A4, and CYP2D6 (high affinity, but low capacity). Following a single 200 mg oral dose to healthy males, the mean peak plasma concentration was 50.3 ng/mL (150 nM), reached in 3.74 hours with a half-life of 123.5 days.

12 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Administration of hydroxychloroquine 200 mg TID led to mean plasma concentrations of 460 ng/mL (1,3 μM).61 Serious side effects include irreversible retinal damage, worsening of psoriasis and porphyria, proximal myopathy and neuropathy, neuropsychiatric events (suicidality), hypoglycemia, and life- threatening and fatal cardiomyopathy, including proarrhythmic effects.89 QT prolongation and TdP. Use of hydroxychloroquine for the treatment of lupus erythematosus has been associated with occasional reports of QT interval prolongation and TdP.90-93 In their recent study using hydroxychloroquine in combination with azithromycin, Chorin et al., observed QTc increases of 40 msec or more in 30% of their patients; in 11% of their 84 patients, QTc increased to more than

55 500msec. CredibleMeds® has classified hydroxychloroquine as a “Known Risk” drug fro TdP. K/ Cmax, K/

Cmax free and Long QT-JT index also identify hydroxychloroquine as a high-risk drug for drug-induced LQTS. Lopinavir/ritonavir. The combination of lopinavir/ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 14 years and older.94 When administered alone, lopinavir is a low affinity CYP3A4 substrate with a low oral bioavailability. As a high affinity substrate of CYP3A4, ritonavir is coadministered to inhibit the first pass metabolism of lopinavir and increases its plasma concentrations by about 10-fold. Under such conditions, lopinavir peak plasma concentrations reach about 10 μg/ml (15.9 μM) after an 800 mg dose. For its part, ritonavir has a bioavailability of 85%, and peak plasma concentrations of about 11 μg/mL (15.5 μM) are observed after administration of a 600 mg oral dose.95,96 Major side-effects associated with lopinavir/ritonavir combination are pancreatitis, hepatotoxicity, new onset of diabetes, immune restitution syndrome, increase in triglycerides and total cholesterol, and fat redistribution.94 Importantly, because of strong CYP3A4 inhibition, major drug-drug interactions are observed with other CYP3A4 substrates.97-101

QT prolongation and TdP. Lopinavir and ritonavir are associated with significant blockade of hERG (IKr) channel102 (Table 1) and cases of TdP have been registered in the FAERS database (Table 3). The monograph of the product also states that cases of QT interval prolongation and TdP have been reported although causality of lopinavir/ritonavir combination could not be established. CredibleMeds® lists the drug under the category “Possible Risk”, while other indices list this combination under High Risk (Table 1). Remdesivir. Remdesivir is an investigational antiviral compound undergoing clinical trials in China, the United States, and the United Kingdom as a potential treatment for COVID-19. Remdesivir, originally tested in Ebola patients, is not yet licensed or approved anywhere globally and has not been

13 medRxiv preprint doi: https://doi.org/10.1101/2020.04.21.20066761; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

demonstrated to be safe or effective for any use.103-105 Remdesivir is a single stereoisomer monophosphoramidate prodrug of a nucleoside analog. After hydrolysis, its metabolite (GS-441524 monophosphate) undergoes, inside the cells, a subsequent rapid conversion to the pharmacologically active nucleoside triphosphate form GS-443902. In vitro, remdesivir also undergoes metabolism by CYP2C8, CYP2D6 and CYP3A4. It is not suitable for oral delivery because of its poor hepatic stability.106 Peak plasma concentrations reached 9.0 μM following administration of a 200 mg intravenous infusion over 30 min.106 QT prolongation and TdP. Very little is known at this stage about the risk of drug-induced LQTS by

remdesivir. An IC50 of 28.9 mM has been estimated in vitro for block of hERG (IKr) (Table 1). Calculated

values for K/ Cmax, K/ Cmax free, and Long QT-JT index indicate that remdesivir use could carry a significant risk, especially if its intravenous administration leads to high peak levels. Therefore, close monitoring on the QT interval appears warranted.

CONCLUSION

In brief, most proposed drugs to be used off-label and repurposed for the treatment of COVID-19 are associated with a significant risk of drug-induced LQTS. Therefore, mandatory monitoring of the QT interval should be performed, as indicated by the current preliminary studies. Such monitoring could be easily performed for hospitalized patients but would require the use of biodevices for outpatients initiated on these drugs. Experimental COVID-19 use with mandatory monitoring is defensible because the benefits of using some of the proposed drugs could outweigh the risks. Key considerations supporting their use are:

1 The duration of use for these medications in COVID-19 is shorter than their original indication (chronic vs five to ten days) thus, only a short-term monitoring would be required.

2 The overall potential population-benefits of those drugs if proven to be effective for COVID-19 compared to the number of patients at high risk for QT prolongation. In addition to monitoring of the QT interval, samples should be collected and biobank created to support research effort in the present and future times. It is recognized that polymorphisms in genes regulating the pharmacokinetics and pharmacodynamics pathways of these drugs may impact an individual’s drug response and consequently, the overall outcomes. The risk-benefit assessment for the use of these drugs remains unclear since benefits are currently anticipated, not proven, but the clinical experience with several of these drugs shows significant risk of toxicity and adverse drug events.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. References

1. Centers for Disease Control and Prevention. 2009 H1N1 Pandemic (H1N1pdm09 virus): CDC; 2019 [updated June 11, 2019. Available from: https://www.cdc.gov/flu/pandemic-resources/2009-h1n1-pandemic.html. 2. World Health Organization. Severe Acute Respiratory Syndrome 2020 [Available from: http://www.emro.who.int/health-topics/severe- doi: acute-respiratory-syndrome/. https://doi.org/10.1101/2020.04.21.20066761 3. World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV): World Health Organization. November 2019. https://www.who.int/emergencies/mers-cov/en/. 4. World Health Organization. Coronavirus disease (COVID-19) Pandemic: World Health Organization. 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019. 5. World Health Organization. MERS Situation Update 2019. November 2019. http://applications.emro.who.int/docs/EMRPUB-CSR-241- All rightsreserved.Noreuseallowedwithoutpermission. 2019-EN.pdf?ua=1&ua=1&ua=1. 6. Adhanom T. WHO Director-General's opening remarks at the media briefing on COVID-19 World Health Organization 2020. March 11, 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. 7. Johns Hopkins University and Medicine. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University [World Map]. 2020. April 13, 2020. https://coronavirus.jhu.edu/map.html. 8. U.S. National Library of Medicine. ClinicalTrials.gov: U.S. National Library of Medicine. April 13, 2020. ; https://clinicaltrials.gov/ct2/results?cond=COVID-19. this versionpostedApril24,2020. 9. Al Rihani SB, Deodhar M, Michaud V, et al. Potential COVID-19 Treatment Options (Off-label: Tabula Rasa HealthCare. April 14, 2020. http://www.trhc.spprdi.com/covid-19-treatment-options 10. Simpson T, Kovacs, RJ, Stecker, EC. Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19. Cardiology Magazine. 2020 March 29, 2020. 11. MIchaud V, Turgeon J, Al Rihani S, Deodhar M. Simulation of Risk of Adverse Drug Events Associated With the Initiation of Drugs Repurposed for the Treatment of COVID-19 in Frail Elderly Adults With Polypharmacy: U.S. National Library of Medicine. April 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04339634?term=04339634&recrs=abdefhm&cond=COVID-19&draw=2&rank=1. 12. Dissertenne F. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur. 1966;59:263-72.

13. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III The copyrightholderforthispreprint antiarrhythmic agents. J Gen Physiol. 1990;96(1):195-215. 14. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81(2):299-307. 15. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269(5220):92-5. 16. Roden DM, Hoffman BF. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ Res. 1985;56(6):857-67.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. 17. Turgeon J, Daleau P, Bennett PB, Wiggins SS, Selby L, Roden DM. Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes. Circ Res. 1994;75(5):879-86. 18. Daleau P, Lessard E, Groleau MF, Turgeon J. Erythromycin blocks the rapid component of the delayed rectifier potassium current and

lengthens repolarization of guinea pig ventricular myocytes. Circulation. 1995;91(12):3010-6. doi: 19. Yang L, Liu H, Sun H-Y, Li GR. Intravenous anesthetic propofol inhibits multiple human cardiac potassium channels. Anesthesiology. https://doi.org/10.1101/2020.04.21.20066761 2015;122(3):571-84. 20. Geelen P, Drolet B, Lessard E, Gilbert P, O'Hara GE, Turgeon J. Concomitant Block of the Rapid (IKr) and Slow (IKs) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization. Journal of Cardiovascular Pharmacology and Therapeutics. 1999;4(3):143-50. 21. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause All rightsreserved.Noreuseallowedwithoutpermission. long QT syndrome. Cell. 1995;80(5):795-803. 22. Keating M, Dunn C, Atkinson D, Timothy K, Vincent GM, Leppert M. Consistent linkage of the long-QT syndrome to the Harvey ras-1 locus on chromosome 11. Am J Hum Genet. 1991;49(6):1335-9. 23. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80(5):805-11. 24. Romano C, Gemme G, Pongiglione R. [Rare Cardiac Arrythmias of the Pediatric Age. Ii. Syncopal Attacks Due to Paroxysmal Ventricular

Fibrillation. (Presentation of 1st Case in Italian Pediatric Literature)]. Clin Pediatr (Bologna). 1963;45:656-83. ; 25. Yang KC, Kyle JW, Makielski JC, Dudley SC, Jr. Mechanisms of sudden cardiac death: oxidants and metabolism. Circ Res. this versionpostedApril24,2020. 2015;116(12):1937-55. 26. Ward OC. A New Familial Cardiac Syndrome in Children. J Ir Med Assoc. 1964;54:103-6. 27. Molokhia M, Pathak A, Lapeyre-Mestre M, Caturla L, Montastruc JL. L'Association Francaise des Centres Regionaux de P, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br J Clin Pharmacol. 2008;66(3):386-95. 28. El-Sherif N, Turitto G. Electrolyte disorders and arrhythmogenesis. Cardiol J. 2011;18(3):233-45. 29. Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev. 2010;62(4):760-81. 30. Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004;484(1):41-8. 31. Webster R, Leishman D, Walker D. Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr The copyrightholderforthispreprint Opin Drug Discov Devel. 2002;5(1):116-26. 32. Crump W, Cavero II. QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development. Pharm Sci Technolo Today. 1999;2(7):270-80. 33. Cavero I, Mestre M, Guillon JM, Crumb W. Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias. Expert Opin Pharmacother. 2000;1(5):947-73. 34. International Conference on Harmonisation; guidance on S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals; availability. Notice. Fed Regist. 2005;70(202):61133-4.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. 35. International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice. Fed Regist. 2005;70(202):61134-5. 36. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev

Drug Discov. 2010;9(3):203-14. doi: 37. Bouvy JC, Koopmanschap MA, Shah RR, Schellekens H. The cost-effectiveness of drug regulation: the example of thorough QT/QTc https://doi.org/10.1101/2020.04.21.20066761 studies. Clin Pharmacol Ther. 2012;91(2):281-8. 38. Redfern WS, Carlsson L, Davis AS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58(1):32-45. 39. Kramer J, Obejero-Paz CA, Myatt G, et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep. 2013;3:2100. All rightsreserved.Noreuseallowedwithoutpermission. 40. Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart J. 2014;167(3):292-300. 41. Colatsky T, Fermini B, Gintant G, et al. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress. J Pharmacol Toxicol Methods. 2016;81:15-20. 42. Romero L, Cano J, Gomis-Tena J, et al. In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk. J Chem Inf Model. 2018;58(4):867-78.

43. Patel N, Wisniowska B, Polak S. Virtual Thorough QT (TQT) Trial-Extrapolation of In Vitro Cardiac Safety Data to In Vivo Situation Using ; Multi-Scale Physiologically Based Ventricular Cell-wall Model Exemplified with Tolterodine and Fesoterodine. Aaps j. 2018;20(5):83. this versionpostedApril24,2020. 44. O'Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol. 2011;7(5):e1002061. 45. CredibleMeds [Internet]. 2020. https://www.crediblemeds.org/. 46. Cicali B, Michaud V, Knowlton CH, Turgeon J. Application of a Novel Medication-Related Risk Stratification Strategy to a Self-Funded Employer Population. Benefits Quarterly. 2018;34(2):49-55. 47. Lee W, Windley MJ, Vandenberg JI, Hill AP. In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details. Front Physiol. 2017;8:934. 48. Steffen LE, Knowlton CH, Turgeon J. Abstract 15939: Development of a Drug-specific Long QT-JT Index for Prediction of Drug-induced QT Prolongation. Circulation. 2016. The copyrightholderforthispreprint 49. Steffen LE, Badea, G., Cicali, B., Knowlton, C.H., Turgeon, J. Medication-Specific Long QT-JT Index And Patient-Specific Long QT-JT Score For Assessing Risk Of Torsade De Pointes: Validation In An Ambulatory Population. Clinical Pharmacology & Therapeutics. 2017;101(S1):S48. 50. Turgeon J, Steffen LE, Badea G, Michaud, V. Methods of Treatment Having Reduced Drug-Related Toxicity and Methods of Identifying the Likelihood of Patient Harm Arising from Prescribed Medications. Patent PCT/US2017/033539. United States of America 2017. 51. Hreiche R, Plante I, Drolet B, Morissette P, Turgeon J. Lengthening of cardiac repolarization in isolated guinea pigs hearts by sequential or concomitant administration of two IKr blockers. J Pharm Sci. 2011;100(6):2469-81. 52. Morissette P, Hreiche R, Turgeon J. Drug-induced long QT syndrome and torsade de pointes. Can J Cardiol. 2005;21(10):857-64.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. 53. Simkó J, Csilek A, Karászi J, Lorincz I. Proarrhythmic potential of antimicrobial agents. Infection. 2008;36(3):194-206. 54. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363-72. 55. Chorin E, Dai M, Shulman E, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin.

medRxiv. 2020:2020.04.02.20047050. doi: 56. Wu CI, Postema PG, Arbelo E, et al. SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes. Heart Rhythm. 2020. https://doi.org/10.1101/2020.04.21.20066761 57. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479-87. 58. Steffen LE, Knowlton CH, Turgeon J. Abstract 16114: Risk Identification of Drug-induced Long QT Syndrome Using a Patient-specific Long QT-JT Risk Score. Circulation. 2016;134(suppl_1):A16114-A. 59. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus All rightsreserved.Noreuseallowedwithoutpermission. Disease 2019) Treatment. Circulation. 60. Drug Label. Zithromax® (azithromycin tablets) and (azithromycin for oral suspension). U.S. Food and Drug Administration; 2013. 61. Gautreta P, Lagiera JC, Parolaa P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non- randomized clinical trial International Journal of Antimicrobial Agents. 2020. 62. Drew RH, Gallis HA. Azithromycin--spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy. 1992;12(3):161- 73.

63. Cooper M, Nye K, Andrews J, Wise R. The pharmacokinetics and inflammatory fluid penetration of orally administered azithromycin. ; Journal of Antimicrobial Chemotherapy. 1990;26(4):533-8. this versionpostedApril24,2020. 64. Foulds G, Shepard R, Johnson R. The pharmacokinetics of azithromycin in human serum and tissues. Journal of Antimicrobial Chemotherapy. 1990;25(suppl_A):73-82. 65. Brkljacić N, Gracin S, Prkacin I, Sabljar-Matovinović M, Mrzljak A, Nemet Z. Stevens-Johnson syndrome as an unusual adverse effect of azithromycin. Acta Dermatovenerol Croat. 2006;14(1):40-5. 66. Milberg P, Eckardt L, Bruns HJ, et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther. 2002;303(1):218-25. 67. Huang BH, Wu CH, Hsia CP, Yin Chen, C. Azithromycin-induced torsade de pointes. Pacing and Clinical Electrophysiology. 2007;30(12):1579-82. 68. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the The copyrightholderforthispreprint absence of other known precipitating factors. J Interv Card Electrophysiol. 2007;18(3):243-6. 69. Mayo Clinic. Malaria: Mayo Clinic. December 13, 2018. https://www.mayoclinic.org/diseases-conditions/malaria/diagnosis- treatment/drc-20351190. 70. Drug Label. Aralen® Chloroquine phosphate, USP. U.S. Food and Drug Administration; 2013. 71. Kim KA, Park JY, Lee JS, Lim S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res. 2003;26(8):631-7.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. 72. Projean D, Baune B, Farinotti R, et al. In vitro metabolism of chlororquine: Identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing n-desethylchloroquine formation. Drug Metabolism and Disposition. 2003;31(6):748-54. 73. Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet.

1996;30(4):263-99. doi: 74. Walker O, Salako LA, Alván G, Ericsson O, Sjöqvist F. The disposition of chloroquine in healthy Nigerians after single intravenous and oral https://doi.org/10.1101/2020.04.21.20066761 doses. British journal of clinical pharmacology. 1987;23(3):295-301. 75. Na-Bangchang K, Limpaibul L, Thanavibul A, Tan-Ariya P, Karbwang J. The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria. British journal of clinical pharmacology. 1994;38(3):278-81. 76. Salako LA, Aderounmu AF, Walker O. Influence of route of administration on the pharmacokinetics of chloroquine and desethylchloroquine. Bull World Health Organ. 1987;65(1):47-50. All rightsreserved.Noreuseallowedwithoutpermission. 77. Gustafsson L, Walker O, Alvan G, et al. Disposition of chloroquine in man after single intravenous and oral doses. British journal of clinical pharmacology. 1983;15(4):471-9. 78. Ducharme J, Farinotti R. Clinical Pharmacokinetics and Metabolism of Chloroquine. Clinical Pharmacokinetics. 1996;31(4):257-74. 79. Ademowo OG, Sodeinde O, Walker O. The disposition of chloroquine and its main metabolite desethylchloroquine in volunteers with and without chloroquine-induced pruritus: Evidence for decreased chloroquine metabolism in volunteers with pruritus. Clinical Pharmacology & Therapeutics. 2000;67(3):237-41.

80. Stas P, Faes D, Noyens P. Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine. Int J Cardiol. ; 2008;127(2):e80-2. this versionpostedApril24,2020. 81. Demazière J, Fourcade JM, Busseuil CT, Adeleine P, Meyer SM, Saïssy JM. The hazards of chloroquine self prescription in west Africa. J Toxicol Clin Toxicol. 1995;33(4):369-70. 82. Furuta Y, Takahashi K, Fukuda Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002;46(4):977-81. 83. Kiso M, Takahashi K, Sakai-Tagawa Y, et al. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc Natl Acad Sci U S A. 2010;107(2):882-7. 84. Furuta Y, Takahashi K, Shiraki K, et al. T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res. 2009;82(3):95-102. 85. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-50. The copyrightholderforthispreprint 86. Jin Z, Smith LK, Rajwanshi VK, Kim B, Deval J. The Ambiguous Base-Pairing and High Substrate Efficiency of T-705 (Favipiravir) Ribofuranosyl 5-Triphosphate towards Influenza A Virus Polymerase. PLOS ONE. 2013;8(7):e68347. 87. Madelain V, Nguyen TH, Olivo A, et al. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin Pharmacokinet. 2016;55(8):907-23. 88. Japan Pharmaceutical and Medical Devices Agency. Report on the deliberation results (Favipiravir). Evaluation and Licensing Division, editor. 2011. 89. Drug Label. Plaquenil® hydroxychloroquine sulfate tablets, USP. U.S. Food and Drug Administration; 2018.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. 90. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila). 2006;44(2):173-5. 91. Morgan ND, Patel SV, Dvorkina O. Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. J Clin Rheumatol. 2013;19(5):286-8. doi: 92. O'Laughlin JP, Mehta PH, Wong BC. Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to https://doi.org/10.1101/2020.04.21.20066761 Hydroxychloroquine. Case Rep Cardiol. 2016;2016:4626279. 93. de Olano J, Howland MA, Su MK, Hoffman RS, Biary R. Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med. 2019;37(12):2264.e5-.e8. 94. Drug Label. Kaletra: Highlights of Prescribing Information. U.S. Food and Drug Administration; 2019.

95. Ouedraogo HG, Matteelli A, Sulis G, et al. Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis–HIV co-infected African All rightsreserved.Noreuseallowedwithoutpermission. adult patients also receiving rifabutin 150 or 300 mg three times per week. Annals of Clinical Microbiology and Antimicrobials. 2020;19(1):3. 96. Kityo C, Walker AS, Dickinson L, et al. Pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors in Ugandan HIV-infected adults. Antimicrob Agents Chemother. 2010;54(7):2965-73. 97. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001;344(13):984-96. 98. Vourvahis M, Kashuba AD. Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir. Pharmacotherapy. 2007;27(6):888-909. ;

99. Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. this versionpostedApril24,2020. 1998;35(4):275-91. 100. de Maat MM, Ekhart GC, Huitema AD, Koks CH, Mulder JW, Beijnen JH. Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet. 2003;42(3):223-82. 101. Foisy MM, Yakiwchuk EM, Hughes CA. Induction Effects of Ritonavir: Implications for Drug Interactions. Annals of Pharmacotherapy. 2008;42(7-8):1048-59. 102. Anson BD, Weaver JG, Ackerman MJ, et al. Blockade of HERG channels by HIV protease inhibitors. Lancet. 2005;365(9460):682-6. 103. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):

104. Amirian ES, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for The copyrightholderforthispreprint coronaviruses. One Health. 2020;9:100128. 105. Remdesivir Approval Status 2020. https://www.drugs.com/history/remdesivir.html. 106. European Medicines Agency. Summary on compassionate use (Remdesivir Gilead). In: Division HM, editor. 2020.

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. Funding: This study was made possible by the financial support of employees from Tabula Rasa HealthCare.

doi: https://doi.org/10.1101/2020.04.21.20066761 All rightsreserved.Noreuseallowedwithoutpermission. ; this versionpostedApril24,2020. The copyrightholderforthispreprint

medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. Table 1. Relative indices of drug-induced LQTS risk associated with repurposed drugs used for COVID-19 treatment.

1 2 3 4 5 6 7 Drug name IC50 IKr (μM) Redfern K/Cmax K/Cmax free Romero Colatsky CredibleMeds Long QT-JT Index Azithromycin 1,091 NA 996 1,993 NA NA Known 1,514 Chloroquine 2.5 CAT 4 NA NA Known 3.56 doi:

8 https://doi.org/10.1101/2020.04.21.20066761 Favipivarir 1 mM (IC10) NA ~6 ~10 NA NA NA ~14 Hydroxychloroquine 5 NA 3.7 7.3 NA NA Known 1.01 Lopinavir/Ritonavir 8.6/8.2 NA/NA 0.54/0.2 27/12 NA NA Possible 27/9 Remdesivir 28.9 NA 3.20 26.7 NA NA NA 16.8

1. Redfern et al., Cardiovasc Res. 2003 Apr 1;58(1):32-45. Review (Full text:http://www.phusewiki.org/wiki/images/a/a7/Redfern_Cardiovas_Res_QT_int_2003.pdf All rightsreserved.Noreuseallowedwithoutpermission.

2. K channel block IC50/Cmax. A value less than 10 is considered at high risk of drug-induced LQTS

8. Calculations for the IC50 for IKr block were using 5-toimes the value measured for an IC10 (8.1% diminution in IKr current) The colors used summarize among the various estimators the level of risk: Very High Risk (red), Intermediate to High Risk (dark yellow) and Low Risk (Pale Yellow). ; this versionpostedApril24,2020.

The copyrightholderforthispreprint medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. Table 2. Relative indices of risk associated with a series of drugs known to be associated with a high risk for drug-induced LQTS.

1 2 3 4 5 6 7 Drug name IC50 IKr (μM) Redfern K/Cmax K/Cmax free Romero Colatsky CredibleMed Long QT-JT Index

Astemizole 0.0012 CAT 2 0.15 4.6 Class 1 Intermediate Known 3.7 doi:

Chlorpromazine 1.5 CAT 3 1.4 39 Class 1 Intermediate Known 9.6 https://doi.org/10.1101/2020.04.21.20066761 Cilostazol 13.8 NA 3.8 76 Class 1 NA Known 15.0 Cisapride 0.015 CAT 2 0.12 5.8 Class 1 Intermediate Known 0.58 Clarithromycin 39.3 CAT 4 12 41 Class 1 Intermediate Known 16.3 Clozapine 2.3 NA 1.0 33 Class 2 Intermediate Possible 9.2

Dasatinib 24.5 NA 24 598 Class 2 NA Possible 484 All rightsreserved.Noreuseallowedwithoutpermission. Domperidone 0.057 CAT 4 0.17 2.2 Class 1 Intermediate Known 0.59 Donepezil 0.7 NA 11 233 Class 1 NA Known 58.7 Droperidol 0.028 CAT 2 0.16 1.8 Class 1 Intermediate Known 0.16 Escitalopram 2.6 NA 28 64 NA NA Known 19.2 Halofantrine 0.38 CAT 3 0.03 2.2 Class 1 NA Known 6.4 Haloperidol 0.04 CAT 3 0.75 10.0 Class 1 NA Known 2.63 ; Lapatinib 1.1 NA 0.26 53 Class 2 NA Possible 16.8 this versionpostedApril24,2020. Methadone 3.5 NA 0.86 6.9 Class 1 NA Known 10.6 Ondansetron 0.81 NA 1.2 4.9 Class 1 Intermediate Known 7.4 Pentamidine 1.28 CAT 3 1.7 5.3 NA NA Known 6.6 Pimozide 0.015 CAT 3 0.28 30 NA Intermediate Known 4.15 Propofol 30 (IKs) NA 1.7 57 NA NA Known 9.9 Risperidone 0.261 CAT 5 2.1 21 Class 2 Intermediate Conditional 8.4 Terfenadine 0.016 CAT 2 1.7 55 Class 1 Intermediate Known 2.75 Thioridazine 0.500 CAT 3 0.28 0.51 Class 1 NA Known 7.05 Vandetanib 0.400 NA 0.09 0.94 NA High Known 1.45 The copyrightholderforthispreprint

1. Redfern et al., Cardiovasc Res. 2003 Apr 1;58(1):32-45. Review (Full text :http://www.phusewiki.org/wiki/images/a/a7/Redfern_Cardiovas_Res_QT_int_2003.pdf

2. K channel block IC50/Cmax. A value less than 10 is considered at high risk of drug-induced LQTS

3. K channel bloc IC50/Cmax free drug. A value les than 100 is considered at high risk of drug-induced LQTS 4. Romero et al., .J Chem Inf Model. 2018 Apr 23;58(4):867-878. 5. Colatsky et al., J Pharmacol Toxicol Methods 2016;81, 15-20 6. Woosley and Romero. AZCERT, Inc. 1822 Innovation Park Dr. Oro Valley, AZ 85755; www.Crediblemeds.org 7. Steffen et al., American Heart Association Annual Meeting Scientific Sessions. Circulation 2016;134:A15939 The colors used summarize among the various estimators the level of risk: Very High Risk (red), Intermediate to High Risk (dark yellow) and Low Risk (Pale Yellow). medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. Table 3. Number of arrhythmogenic adverse drug events reported by the FDA Adverse Event Reporting System for repurposed drugs used for COVID-19 treatment and drugs known to be associated with a high risk for drug-induced LQTS. doi: https://doi.org/10.1101/2020.04.21.20066761 All rightsreserved.Noreuseallowedwithoutpermission. ; this versionpostedApril24,2020. The copyrightholderforthispreprint medRxiv preprint

DRUG NAME All terms1 VT/VF/TdP/LQTS2 VT/VF/VA/VFL/VT3 TdP/LQTS4 CA/C-RA5 (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. AZITHROMYCIN 790 168 115 53 171 CHLOROQUINE 129 40 28 12 36

HYDROXYCHLOROQUINE 240 73 38 35 48 doi:

LOPINAVIR/RITONAVIR 501 42 30 12 90 https://doi.org/10.1101/2020.04.21.20066761 RITONAVIR 206 35 28 7 81 CHLORPROMAZINE 48 0 3 0 9 CILOSTAZOL 298 60 79 20 52 CISAPRIDE 1026 162 173 77 38 All rightsreserved.Noreuseallowedwithoutpermission. CLARITHROMYCIN 769 182 113 118 127 CLOZAPINE 2530 29 55 6 686 DASATINIB 180 7 9 2 57 DOMPERIDONE 21 5 7 1 0 DONEPEZIL 1108 157 103 121 172

DROPERIDOL 26 7 11 2 3 ; this versionpostedApril24,2020. ESCITALOPRAM 838 56 59 28 128 HALOFANTRINE 4 1 1 1 1 HALOPERIDOL 723 144 81 100 176 LAPATINIB 251 7 8 3 47 METHADONE 1537 220 114 174 661 ONDANSETRON 854 191 184 125 192 PENTAMIDINE 2 0 0 0 1 PIMOZIDE 33 7 6 4 7 The copyrightholderforthispreprint PROPOFOL 675 133 198 31 348 RISPERIDONE 1608 131 108 67 324 THIORIDAZINE 56 6 9 1 10 VANDETANIB 93 1 1 1 2

1. “All terms” refers to the following terms included in the query: Electrocardiogram QT prolonged, Long QT syndrome, Long QT syndrome congenital, Torsade de pointes, Ventricular tachycardia, Cardiac arrest, Cardiac death, Cardiac fibrillation, Cardio-respiratory arrest, Electrocardiogram repolarization abnormality, Electrocardiogram U wave inversion, medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity. Electrocardiogram U wave present, Electrocardiogram U-wave abnormality, Loss of consciousness, Multiple organ dysfunction syndrome, Sudden cardiac death, Sudden death, Syncope, Ventricular arrhythmia, Ventricular fibrillation, Ventricular flutter, Ventricular tachyarrhythmia. 2. Terms included in the query comprised: Ventricular Tachycardia (VT), Ventricular fibrillation (VF), Torsade de pointes (TdP), Long QT Syndrome (LQTS), Ventricular arrhythmia, ventricular flutter, Cardiac fibrillation. 3. Terms included in the query comprised: Ventricular Tachycardia (VT), Ventricular fibrillation (VF), Ventricular arrhythmia (VA), Ventricular flutter (VFL), Cardiac fibrillation (CF). doi: 4. Terms included in the query comprised: Long QT Syndrome (LQTS), Torsade de pointes (TdP) 5. Terms included in the query comprised: Cardiac arrest (CA), Cardio-respiratory arrest (C-RA) https://doi.org/10.1101/2020.04.21.20066761

All rightsreserved.Noreuseallowedwithoutpermission. ; this versionpostedApril24,2020. The copyrightholderforthispreprint medRxiv preprint (which wasnotcertifiedbypeerreview)istheauthor/funder,whohasgrantedmedRxivalicensetodisplaypreprintinperpetuity.

doi: https://doi.org/10.1101/2020.04.21.20066761 All rightsreserved.Noreuseallowedwithoutpermission. ; this versionpostedApril24,2020. The copyrightholderforthispreprint